G. Defraene

Quantitative radiomics studies for tissue characterization: a review of technology and methodological procedures

Quantitative analysis of tumour characteristics based on medical imaging is an emerging field of research. In recent years, quantitative imaging features derived from CT, positron emission tomography and MR scans were shown to be of added value in the prediction of outcome parameters in oncology, in what is called the radiomics field. However, results might be difficult to compare owing to a lack of standardized methodologies to conduct quantitative image analyses. In this review, we aim to present an overview of the current challenges, technical routines and protocols that are involved in quantitative imaging studies. The first issue that should be overcome is the dependency of several features on the scan acquisition and image reconstruction parameters. Adopting consistent methods in the subsequent target segmentation step is evenly crucial. To further establish robust quantitative image analyses, standardization or at least calibration of imaging features based on different feature extraction settings is required, especially for texture- and filter-based features. Several open-source and commercial software packages to perform feature extraction are currently available, all with slightly different functionalities, which makes benchmarking quite challenging. The number of imaging features calculated is typically larger than the number of patients studied, which emphasizes the importance of proper feature selection and prediction model-building routines to prevent overfitting. Even though many of these challenges still need to be addressed before quantitative imaging can be brought into daily clinical practice, radiomics is expected to be a critical component for the integration of image-derived information to personalize treatment in the future.

Intensity-Modulated Radiotherapy for Locally Advanced Non–Small-Cell Lung Cancer: A Dose-Escalation Planning Study

PURPOSE To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). METHODS AND MATERIALS For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). RESULTS IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. CONCLUSION In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT.

Quantification of radiation-induced lung damage with CT scans: The possible benefit for radiogenomics

Abstract Background. Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed. Methods. Hounsfield unit (HU) changes before versus three months post-radiotherapy were correlated per voxel with the radiotherapy dose in 95 lung cancer patients. Deformable registration was used to register pre- and post-CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2. Results. Radiation dose was linearly correlated with the change in HU (mean R2 = 0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo- radiotherapy were observed. In the whole patient group, 33/95 (34.7%) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3%) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1%) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. Conclusions. HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

CT characteristics allow identification of patient-specific susceptibility for radiation-induced lung damage

BACKGROUND AND PURPOSE There is a huge difference in radiosensitivity of lungs between patients. The present study aims to identify and quantify patient-specific radiosensitivity based on a single pre-treatment CT scan. MATERIALS AND METHODS 130 lung cancer patients were studied: 60 stereotactic ablative radiotherapy (SABR) treatments and 70 conventional treatments (20 and 30 patients from external datasets, respectively). A 3month-follow-up scan (CT3M) was non-rigidly registered to the planning CT scan (CT0). Changes in Hounsfield Units (ΔHU=HU3M-HU0) inside lung subvolumes were analyzed per dose bin of 5Gy. ΔHU was modeled as a function of local dose using linear and sigmoidal fits. Sigmoidal fit parameters ΔHUmax (saturation level) and D50 (dose corresponding to 50% of ΔHUmax) were collected for all patients. RESULTS Sigmoidal fits outperformed linear fits in the SABR groups for the majority of patients. Sigmoidal dose-responses were also observed in both conventional groups but to a lesser extent. Distributions of D50 and ΔHUmax showed a large variation between patients in all datasets. Higher baseline lung density (p<0.001) was prognostic for higher ΔHUmax in one SABR group. No prognostic factors were found for D50. CONCLUSIONS Baseline CT characteristics are prognostic for radiation-induced lung damage susceptibility.

IMRT-based optimization approaches for volumetric modulated single arc radiotherapy planning

This paper reports on an evaluation of 5 RapidArc optimization approaches vs IMRT. This study includes 11 patients with adenocarcinoma of the prostate. Rectal Normal Tissue Complication Probability is used as a constraint in a dose escalation. RapidArc rectal NTCPs are lower than those of IMRT (p = 0.007). This allows a mean dose escalation of 2.1 Gy([0.7 Gy,3.5 Gy]).

Out-of-field contributions for IMRT and volumetric modulated arc therapy measured using gafchromic films and compared to calculations using a superposition/convolution based treatment planning system.

PURPOSE To quantify the whole-body-dose delivered during the application of new techniques and compare them to the results obtained by treatment planning systems. The ultimate goal being the use of planning data in combination with complication data to assess the impact of low doses of ionizing radiation. METHODS A film technique using gafchromic films to assess low doses was used on simplified phantoms and compared to data from treatment planning systems as well as a simplified whole body dose calculation system (Peridose). The types of treatment include open fields, intensity modulated radiation therapy (IMRT) and volumetric arc treatments. The film measurements were confirmed using TLDs in Alderson phantoms. In addition neutron contributions were measured as these are not taken into account in the current modern treatment planning systems, but can add significantly to the patients whole body dose. RESULTS Dose outside of the treatment plane diminished to 1% of the prescribed dose, this for open fields, IMRT and rotational treatments alike. Noteworthy was an increase at about 20cm from the central plane in IMRT, and in a more limited fashion for volumetric modulated arc treatment. In open fields this was not observed. Treatment planning systems were good at determining the out-of-field doses of single field treatments. In complex plans the TPS underestimated the dose to the patient. At distances greater than 20cm from the field edge, these systems did not predict any dose. The Peridose program performed well in the case of classical treatments. In the case of IMRT treatments, the overall evolution of the dose as a function of the distance to the field was well-modeled. However, an over estimation of the order of 60-80% was observed, leaving the possibility for a corrective factor based on a point measurement. Dose levels over the whole body were of the order 100mGy or higher over a complete treatment for the more complex treatments. Neutron dose levels were of the order single digit mSv for 10MV treatments. For 18MV the level of neutron contribution was in agreement with recent publications, corroborating reports that the dose from neutrons is lower than previously reported.

The photon dose calculation algorithm used in breast radiotherapy has significant impact on the parameters of radiobiological models.

The comparison of the pencil beam dose calculation algorithm with modified Batho heterogeneity correction (PBC‐MB) and the analytical anisotropic algorithm (AAA) and the mutual comparison of advanced dose calculation algorithms used in breast radiotherapy have focused on the differences between the physical dose distributions. Studies on the radiobiological impact of the algorithm (both on the tumor control and the moderate breast fibrosis prediction) are lacking. We, therefore, investigated the radiobiological impact of the dose calculation algorithm in whole breast radiotherapy. The clinical dose distributions of 30 breast cancer patients, calculated with PBC‐MB, were recalculated with fixed monitor units using more advanced algorithms: AAA and Acuros XB. For the latter, both dose reporting modes were used (i.e., dose‐to‐medium and dose‐to‐water). Next, the tumor control probability (TCP) and the normal tissue complication probability (NTCP) of each dose distribution were calculated with the Poisson model and with the relative seriality model, respectively. The endpoint for the NTCP calculation was moderate breast fibrosis five years post treatment. The differences were checked for significance with the paired t‐test. The more advanced algorithms predicted a significantly lower TCP and NTCP of moderate breast fibrosis then found during the corresponding clinical follow‐up study based on PBC calculations. The differences varied between 1% and 2.1% for the TCP and between 2.9% and 5.5% for the NTCP of moderate breast fibrosis. The significant differences were eliminated by determination of algorithm‐specific model parameters using least square fitting. Application of the new parameters on a second group of 30 breast cancer patients proved their appropriateness. In this study, we assessed the impact of the dose calculation algorithms used in whole breast radiotherapy on the parameters of the radiobiological models. The radiobiological impact was eliminated by determination of algorithm specific model parameters. PACS numbers: 87.55.dh, 87.55.dkThe comparison of the pencil beam dose calculation algorithm with modified Batho heterogeneity correction (PBC-MB) and the analytical anisotropic algorithm (AAA) and the mutual comparison of advanced dose calculation algorithms used in breast radiotherapy have focused on the differences between the physical dose distributions. Studies on the radiobiological impact of the algorithm (both on the tumor control and the moderate breast fibrosis prediction) are lacking. We, therefore, investigated the radiobiological impact of the dose calculation algorithm in whole breast radiotherapy. The clinical dose distributions of 30 breast cancer patients, calculated with PBC-MB, were recalculated with fixed monitor units using more advanced algorithms: AAA and Acuros XB. For the latter, both dose reporting modes were used (i.e., dose-to-medium and dose-to-water). Next, the tumor control probability (TCP) and the normal tissue complication probability (NTCP) of each dose distribution were calculated with the Poisson model and with the relative seriality model, respectively. The endpoint for the NTCP calculation was moderate breast fibrosis five years post treatment. The differences were checked for significance with the paired t-test. The more advanced algorithms predicted a significantly lower TCP and NTCP of moderate breast fibrosis then found during the corresponding clinical follow-up study based on PBC calculations. The differences varied between 1% and 2.1% for the TCP and between 2.9% and 5.5% for the NTCP of moderate breast fibrosis. The significant differences were eliminated by determination of algorithm-specific model parameters using least square fitting. Application of the new parameters on a second group of 30 breast cancer patients proved their appropriateness. In this study, we assessed the impact of the dose calculation algorithms used in whole breast radiotherapy on the parameters of the radiobiological models. The radiobiological impact was eliminated by determination of algorithm specific model parameters. PACS numbers: 87.55.dh, 87.55.dk.

Dosimetric adaptive IMRT driven by fiducial points

PURPOSE Intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy have become standard treatments but are more sensitive to anatomical variations than 3D conformal techniques. To correct for inter- and intrafraction anatomical variations, fast and easy to implement methods are needed. Here, the authors propose a full dosimetric IMRT correction that finds a compromise in-between basic repositioning (the current clinical practice) and full replanning. It simplifies replanning by avoiding a recontouring step and a full dose calculation. It surpasses repositioning by updating the preoptimized fluence and monitor units (MU) using a limited number of fiducial points and a pretreatment (CB)CT. To adapt the fluence the fiducial points were projected in the beams eye view (BEV). To adapt the MUs, point dose calculation towards the same fiducial points were performed. The proposed method is intrinsically fast and robust, and simple to understand for operators, because of the use of only four fiducial points and the beam data based point dose calculations. METHODS To perform our dosimetric adaptation, two fluence corrections in the BEV are combined with two MU correction steps along the beams path. (1) A transformation of the fluence map such that it is realigned with the current target geometry. (2) A correction for an unintended scaling of the penumbra margin when the treatment beams scale to the current target size. (3) A correction for the target depth relative to the body contour and (4) a correction for the target distance to the source. The impact of the correction strategy and its individual components was evaluated by simulations on a virtual prostate phantom. This heterogeneous reference phantom was systematically subjected to population based prostate transformations to simulate interfraction variations. Additionally, a patient example illustrated the clinical practice. The correction strategy was evaluated using both dosimetric (CTV mean dose, conformity index) and clinical (tumor control probability, and normal tissue complication probability) measures. RESULTS Based on the current experiments, the intended target dose and tumor control probability could be assured by the proposed method (TCP ≥ TCP(intended)). Additionally, the conformity index error was more than halved compared to the current clinical practice (ΔCI(95%) from 40% to 16%) resulting in improved organ at risk protection. All the individual correction steps had an added value to the full correction. CONCLUSIONS A limited number of fiducial points (no organ contours required) and an in-room (CB)CT are sufficient to perform a full dosimetric correction for IMRT plans. In the presence of interfraction variation, the corrected plans show superior dose distributions compared to our current clinical practice.

Online adaptation and verification of VMAT

PURPOSE This work presents a method for fast volumetric modulated arc therapy (VMAT) adaptation in response to interfraction anatomical variations. Additionally, plan parameters extracted from the adapted plans are used to verify the quality of these plans. The methods were tested as a prostate class solution and compared to replanning and to their current clinical practice. METHODS The proposed VMAT adaptation is an extension of their previous intensity modulated radiotherapy (IMRT) adaptation. It follows a direct (forward) planning approach: the multileaf collimator (MLC) apertures are corrected in the beams eye view (BEV) and the monitor units (MUs) are corrected using point dose calculations. All MLC and MU corrections are driven by the positions of four fiducial points only, without need for a full contour set. Quality assurance (QA) of the adapted plans is performed using plan parameters that can be calculated online and that have a relation to the delivered dose or the plan quality. Five potential parameters are studied for this purpose: the number of MU, the equivalent field size (EqFS), the modulation complexity score (MCS), and the components of the MCS the aperture area variability (AAV) and the leaf sequence variability (LSV). The full adaptation and its separate steps were evaluated in simulation experiments involving a prostate phantom subjected to various interfraction transformations. The efficacy of the current VMAT adaptation was scored by target mean dose (CTVmean), conformity (CI95%), tumor control probability (TCP), and normal tissue complication probability (NTCP). The impact of the adaptation on the plan parameters (QA) was assessed by comparison with prediction intervals (PI) derived from a statistical model of the typical variation of these parameters in a population of VMAT prostate plans (n = 63). These prediction intervals are the adaptation equivalent of the tolerance tables for couch shifts in the current clinical practice. RESULTS The proposed adaptation of a two-arc VMAT plan resulted in the intended CTVmean (Δ ≤ 3%) and TCP (ΔTCP ≤ 0.001). Moreover, the method assures the intended CI95% (Δ ≤ 11%) resulting in lowered rectal NTCP for all cases. Compared to replanning, their adaptation is faster (13 s vs 10 min) and more intuitive. Compared to the current clinical practice, it has a better protection of the healthy tissue. Compared to IMRT, VMAT is more robust to anatomical variations, but it is also less sensitive to the different correction steps. The observed variations of the plan parameters in their database included a linear dependence on the date of treatment planning and on the target radius. The MCS is not retained as QA metric due to a contrasting behavior of its components (LSV and AAV). If three out of four plan parameters (MU, EqFS, AAV, and LSV) need to lie inside a 50% prediction interval (3/4-50%PI), all adapted plans will be accepted. In contrast, all replanned plans do not meet this loose criterion, mainly because they have no connection to the initially optimized and verified plan. CONCLUSIONS A direct (forward) VMAT adaptation performs equally well as (inverse) replanning but is faster and can be extended to real-time adaptation. The prediction intervals for the machine parameters are equivalent to the tolerance tables for couch shifts in the current clinical practice. A 3/4-50%PI QA criterion accepts all the adapted plans but rejects all the replanned plans.

CONFORMAL LOCOREGIONAL BREAST IRRADIATION WITH AN OBLIQUE PARASTERNAL PHOTON FIELD TECHNIQUE

We evaluated an isocentric technique for conformal irradiation of the breast, internal mammary, and medial supra-clavicular lymph nodes (IM-MS LN) using the oblique parasternal photon (OPP) technique. For 20 breast cancer patients, the OPP technique was compared with a conventional mixed-beam technique (2D) and a conformal partly wide tangential (PWT) technique, using dose-volume histogram analysis and normal tissue complication probabilities (NTCPs). The 3D techniques resulted in a better target coverage and homogeneity than did the 2D technique. The homogeneity index for the IM-MS PTV increased from 0.57 for 2D to 0.90 for PWT and 0.91 for OPP (both p < 0.001). The OPP technique was able to reduce the volume of heart receiving more than 30 Gy (V(30)), the cardiac NTCP, and the volume of contralateral breast receiving 5 Gy (V(5)) compared with the PWT plans (all p < 0.05). There is no significant difference in mean lung dose or lung NTCP between both 3D techniques. Compared with the PWT technique, the volume of lung receiving more than 20 Gy (V(20)) was increased with the OPP technique, whereas the volume of lung receiving more than 40 Gy (V(40)) was decreased (both p < 0.05). Compared with the PWT technique, the OPP technique can reduce doses to the contralateral breast and heart at the expense of an increased lung V(20).